Self-administered contraceptive injection of oily solution

ABSTRACT

The subject invention provides a pharmaceutical formulation in the form of an oily solution for injection to a subject comprising a contraceptively and/or therapeutically effective amount of a long-acting progestogen and a contraceptively and/or therapeutically effective amount of a long-acting androgen dissolved in a pharmaceutically acceptable oily medium wherein the injection is administered by the subject itself with a needle-less device, a mini-needle device or a pre-filled subcutaneous syringe.

FIELD OF THE INVENTION

The subject invention concerns the field of (male and female)contraception and (male and female) hormone replacement therapy (HRT).

BACKGROUND

Contraceptive methods for men and women are important for worldwidereproductive health.

However, no effective and efficient methods of male contraception are asof yet available.

Male contraception seeks to suppress spermatogenesis through thesuppression of the gonadotropins luteinizing hormone (LH) andfollicle-stimulating hormone (FSH). This results in a depletion ofintratesticular testosterone and cessation of spermatogenesis.

Administration of progestagen results in a dose dependent suppression ofpituitary gonadotrophins and consequently, a decrease in testosteronelevels and a reversible inhibition of spermatogenesis. An exogenousandrogen is required to compensate for the reduced testosterone levels.In the same way, male HRT can be accomplished, resulting in replacementof testosterone by an exogenous androgen which is safer on the prostatethan endogenous testosterone.

The use of progestogens together with androgens for use as malecontraceptives is known (Guerin and Rollet (1988), International Journalof Andrology 11, 187-199).

However, the use of specific esters of etonogestrel for malecontraception and HRT has not been suggested.

In addition, the use of progestogens together with estrogens for use infemale contraception is known (M. Tausk, J. H. H. Thijssen, Tj. B. vanWimersma Greidanus, “Pharmakologie der Hormone”, Georg Thieme Verlag,Stuttgart, 1986).

Progestagens are widely used for female contraception and in female HRT.In contraception, the combination progestagen-estrogen oralcontraceptives are the most widely used. Administration of such acombination results in a number of effects: it blocks ovulation, itinterferes with phasic development of the endometrium which decreasesthe chance for successful implantation, and it causes the cervical mucusto become so viscous that it hinders sperm penetration. Mostprogestagen-only-pills (POP's) aim at the last mentioned effect only.

Female HRT is aimed at suppletion of endogenous estrogen for thetreatment of peri- and postmenopausal complaints (hot flushes, vaginaldryness), and for prevention of symptoms of long-term estrogendeficiency. The latter include osteoporosis, coronary artery disease,urogenital incontinence, and possibly also Alzheimer's disease andcolorectal cancer. A drawback of long-term unopposed estrogenadministration is the associated increase in endometrium proliferation,which in turn may increase the risk of endometrial cancer. For thatreason, progestagens are co-administered in long-term regimes, becauseof their ability to reduce the proliferative activity of endometrialepithelium and to induce secretory conversion.

However, the use of specific esters of etonogestrel for femalecontraception, female HRT and treatment/prevention of gynaecologicaldisorders has not been suggested.

There are also no disclosures of a male or female contraceptive/HRTsolution for self-injection which would result in high compliancelevels. Compliance is probably the most important factor incontraceptive use; without good compliance even the best contraceptivesare without effect.

There is therefore a need for a male and female contraceptive which willhave a high compliance rate in male and female subjects undergoingcontraception.

High compliance depends on infrequent, painless administration withoutside effects and without local site reactions.

SUMMARY OF THE INVENTION

The subject invention provides a pharmaceutical formulation in the formof an oily solution for injection to a subject comprising acontraceptively and/or therapeutically effective amount of a long-actingprogestogen and a contraceptively and/or therapeutically effectiveamount of a long-acting androgen dissolved in a pharmaceuticallyacceptable oily medium wherein the injection is administered by thesubject itself with a needle-less device, a mini-needle device or apre-filled subcutaneous syringe and wherein the injectable volume of thesolution is less than 1 milliliter.

The subject invention further contemplates a use of a long-actingprogestogen and a long-acting androgen dissolved in a pharmaceuticallyacceptable oily medium for the manufacture of an injectablepharmaceutical formulation for male contraception wherein the injectionis administered with a needle-less device, a mini-needle device or apre-filled subcutaneous syringe and wherein the injectable volume of thesolution is less than 1 milliliter.

The subject invention also provides a male contraceptive kit forinjection comprising a long-acting progestogen and a long-actingandrogen dissolved in an oily medium wherein the injection isadministered by the subject itself with a needle-less device, amini-needle device or a pre-filled subcutaneous syringe and wherein theinjectable volume of the solution is less than 1 milliliter.

The subject invention further contemplates a method of malecontraception comprising injecting a solution comprising acontraceptively and/or therapeutically-effective amount of a long-actingprogestogen and a contraceptively and/or therapeutically effectiveamount of a long-acting androgen dissolved in an oily medium to asubject wherein the injection is administered by the subject itself witha needle-less device, a mini-needle device or a pre-filled subcutaneoussyringe and wherein the injectable volume of the solution is less than 1milliliter.

The subject invention also contemplates a pharmaceutical formulation inthe form of an oily solution for injection to a subject comprising acontraceptively and/or therapeutically effective amount of a long-actingprogestogen and a contraceptively and/or therapeutically effectiveamount of an estrogen dissolved in a pharmaceutically acceptable oilymedium wherein the injection is administered by the subject itself witha needle-less device, a mini-needle device or a pre-filled subcutaneoussyringe.

FIGURES

FIG. 1

Chemical structures of etonogestrel heptanoate (etonogestrel enanthate),etonogestrel nonanoate, etonogestrel decanoate, etonogestrelundecanoate, etonogestrel dodecanoate, etonogestrel tridecanoate, andetonogestrel pentadecanoate.

FIG. 2 a

Effect of one intramuscular (IM) injection of etonogestrel, etonogestrelheptanoate (etonogestrel enanthate), etonogestrel nonanoate andetonogestrel undecanoate on plasma levels of etonogestrel in male intactrabbits. Means and SEM of N=3.

FIG. 2 b

Effect of one intramuscular (IM) injection of etonogestrel heptanoate(etonogestrel enanthate), etonogestrel nonanoate, etonogestreldecanoate, etonogestrel undecanoate, etonogestrel dodecanoate,etonogestrel tridecanoate on plasma levels of etonogestrel in maleintact rabbits. Means and SEM of N=3.

FIG. 3

Chemical structure of MENT-undecanoate, MENT-buciclate, testosteroneheptanoate (testosterone enanthate) and testosterone undecanoate.

FIG. 4

Time dependent effects of one s.c injection of 20 mg/kg ofMENT-undecanoate (MENT-U), MENT-buciclate (MENT-B), testosteroneheptanoate (testosterone enanthate, TE) and testosterone undecanoate(TU) in castrated male rabbits on serum MENT or testosterone (T).Results are means of N=3.

FIG. 5

Pharmacokinetics of testosterone enanthate, testosterone undecanoate andtestosterone buciclate after one IM injected in male hypogonadal menwith indicated doses on the plasma levels of serum testosterone. Normalrange of serum testosterone is indicated with a dashed line. Derivedfrom E. Nieschlag and H. M. Behre. Testosterone Therapy. In: Andrology,Male reproductive health and dysfunction., edited by E. Nieschlag and H.M. Behre, Berlin, Heidelberg and New York:Springer-Verlag, 1997, p.297-309.

FIG. 6: completeness of injection

FIG. 7: pain scale

FIG. 8: immediate pain scores

FIG. 9: injection sensation scale

FIG. 10: injection sensation

FIG. 11: local site reactions after 2 hours

FIG. 12: local site reactions after 24 hours

FIG. 13: local site reactions after 5-7 days

FIG. 14: subject preference

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a pharmaceutical formulation in the formof an oily solution for injection to a subject comprising acontraceptively and/or therapeutically effective amount of a long-actingprogestogen and a contraceptively and/or therapeutically effectiveamount of a long-acting androgen dissolved in a pharmaceuticallyacceptable oily medium wherein the injection is administered by thesubject itself with a needle-less device, a mini-needle device or apre-filled subcutaneous syringe and wherein the injectable volume of thesolution is less than 1 milliliter.

The subject invention further contemplates a use of a long-actingprogestogen and a long-acting androgen dissolved in a pharmaceuticallyacceptable oily medium for the manufacture of an injectablepharmaceutical formulation for male contraception wherein the injectionis administered with a needle-less device, a mini-needle device or apre-filled subcutaneous syringe and wherein the injectable volume of thesolution is less than 1 milliliter.

The subject invention also provides a male contraceptive kit forinjection comprising a long-acting progestogen and a long-actingandrogen dissolved in an oily medium wherein the injection isadministered by the subject itself with a needle-less device, amini-needle device or a pre-filled subcutaneous syringe and wherein theinjectable volume of the solution is less than 1 milliliter.

The subject invention further contemplates a method of malecontraception comprising injecting a solution comprising acontraceptively and/or therapeutically-effective amount of a long-actingprogestogen and a contraceptively and/or therapeutically effectiveamount of a long-acting androgen dissolved in an oily medium to asubject wherein the injection is administered by the subject itself witha needle-less device, a mini-needle device or a pre-filled subcutaneoussyringe and wherein the injectable volume of the solution is less than 1milliliter.

Similarly, a pharmaceutical formulation in the form of an oily solutionfor injection to a subject can be prepared comprising a contraceptivelyand/or therapeutically effective amount of a long-acting progestogen anda contraceptively and/or therapeutically effective amount of along-acting estrogen dissolved in a pharmaceutically acceptable oilymedium wherein the injection is administered by the subject itself witha needle-less device, a mini-needle device or a pre-filled subcutaneoussyringe and wherein the injectable volume of the solution is less than 1milliliter.

In a preferred embodiment, the long acting progestogen is an ester witha fatty chain length of C7 to C15, preferably an ester of a progestogenselected from the group consisting of ethisterone, norethisterone(norethindrone), dimethisterone, norethynodrel, norgestrienone,lynestrenol, ethynodiol, (levo)norgestrel, desogestrel, gestodene,allylestrenol, etonogestrel and dienogest. In a specific embodiment, theprogestogen is an ester of etonogestrel with a fatty chain length of C10to C12.

In a preferred embodiment, the long-acting androgen is an ester with afatty chain length of C6 to C12, preferably an ester of testosterone oran ester of 7-alpha-methyl-19-nortestosterone (MENT). In a specificembodiment, the ester of 7-alpha-methyl-19-nortestosterone (MENT) isMENT undecanoate.

In a preferred embodiment, it is contemplated that the long-actingprogestogen is an ester of etonogestrel and the long-acting androgen isan ester of 7-alpha-methyl-19-nortestosterone (MENT). In a mostpreferred embodiment, the ester of 7-alpha-methyl-19-nortestosterone(MENT) is MENT undecanoate and the ester of etonogestrel is etonogestrelundecanoate and/or etonogestrel decanoate and/or etonogestreldodecanoate.

It is contemplated that the injection takes place once per month or onceper two months.

The progestogen and testosterone esters can be prepared by dissolving itin a suitable amount of an oily medium, such as arachis oil, oleic acid,castor oil, ethyl undecanoate, almond oil, sesame oil, coconut oil,olive oil, soyabean oil, (purified) tri-glycerised, propylene glycolesters, ethyl oleate and the like, including mixtures of oils. Theamount of esters that can be dissolved differs per chosen medium, butwill generally be within the range of from 100-400 mg.

In a preferred embodiment it is further contemplated that the oilymedium is arachis oil or ethyl undecanoate.

In a further embodiment, the contraceptively and/or therapeuticallyeffective amount of MENT undecanoate is 50-400 mg and thecontraceptively and/or therapeutically effective amount of etonogestrelester is 25-200 mg. In a more specific embodiment, the contraceptivelyand/or therapeutically effective amount of MENT undecanoate is 50-200 mgand the contraceptively and/or therapeutically effective amount ofetonogestrel ester is 50-100 mg. In a very specific embodiment, thecontraceptively and/or therapeutically effective amount of MENTundecanoate is 100 mg and the contraceptively and/or therapeuticallyeffective amount of etonogestrel ester is 50 mg.

Additives common to injection fluids can be added to the solution ifdesired. Suitable additives are known to the person skilled in the art.Possible additives include liquids that serve to lower the viscosity ofthe formulation, e.g. benzyl alcohol, benzyl benzoate, benzylpropionate, ethyl oleate or ethyl undecanoate. The present invention isfurther described in the following examples which are not in any wayintended to limit the scope of the invention as claimed.

EXAMPLES Example 1 Kinetics of Etonogestrel C7, C9, C10, C11, C12 andC13 Esters in Rabbits

The following etonogestrel esters were prepared and tested in rabbits:

-   -   Etonogestrel heptanoate    -   Etonogestrel nonanoate    -   Etonogestrel decanoate    -   Etonogestrel undecanoate    -   Etonogestrel dodecanoate    -   Etonogestrel tridecanoate

Etonogestrel pentadecanoate was also prepared.

FIG. 1 shows the chemical structure of these compounds.

As a reference, etonogestrel was also included.

Preparation of Etonogestrel Esters

General methodology for the preparation of esters from alcohols can befound in e.g. Greene, T. W. et al, “Protective groups in organicsynthesis”, John Wiley & Sons, NY, 1999 (third edition). Preparation ofesters from tertiary alcohols (like etonogestrel) can be accomplished byseveral techniques, for instance:

1) tertiary alcohol, carboxylic acid, trifluoroacetic acid-anhydride, DE1013284 (1956); 2) tertiary alcohol, acid chloride, pyridine, Watson, T.G. et al, Steroids 41, 255 (1983); 3) tertiary alcohol, acid chloride,TIOEt, Shafiee, A. et al, Steroids 41, 349 (1983), 4) tertiary alcohol,carboxylic acid-anhydride, TsOH, benzene, Johnson, A. L., Steroids, 20,263 (1972); and 5) tertiary alcohol, carboxylic acid-anhydride, DMAP,CH₂Cl₂, Shafiee, A. et al, Steroids 41, 349 (1983).

Preparation of(17α)-13-Ethyl-11-methylene-17-[[(1-oxononyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one(etonogestrel nonanoate)

-   a) A solution of nonanoic acid (1.95 g) in dry toluene (8 ml) was    cooled to 0° C. and treated with trifluoroacetic acid anhydride (2.6    g). After 30 min. stirring,    (17α)-13-ethyl-17-hydroxy-11-methylene-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel, 2.0 g) in dry toluene (15 ml) was added and the    reaction mixture was stirred for 17 h at room temperature. The    reaction mixture was washed with water, a saturated aqueous solution    of sodium hydrogen carbonate, water, and brine. The organic phase    was dried over sodium sulfate and concentrated under reduced    pressure. The residue was purified by column chromatography    (toluene/ethyl acetate 95:5). The product (2.08 g) was dissolved in    ethyl acetate (40 ml), cooled to 0° C., and stirred with aqueous    sodium hydroxide (1 M, 13 ml) for 2 h. The mixture was extracted    with ethyl acetate; the combined organic phases were washed with    ice-cold aqueous sodium hydroxide (1 M), water and brine, dried and    concentrated under reduce pressure. Column chromatography afforded    (17α)-13-ethyl-11-methylene-17-[[(1-oxononyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (1.25 g). ¹H-NMR (CDCl₃): δ 5.89 (m, 1H), 5.08 (bs, 1H), 4.85 (bs,    1H), 2.82 (ddd, 1H, J=14.8, 9.5 and 6.3 Hz), 2.73 (d, 1H, J=12.8    Hz), 2.69-2.19 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.21 (m), 1.15    (m, 1H), 1.05 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Measured    mass [M+H]⁺465.3358. Calculated mass [M+H]⁺465.3363.

In a manner analogous to the procedure described above, etonogestrelheptanoate, etonogestrel decanoate, etonogestrel undecanoate,etonogestrel dodecanoate, etonogestrel tridecanoate, and etonogestrelpentadecanoate were prepared:

-   b)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxoheptyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel heptanoate). ¹H-NMR (CDCl₃): δ 5.89 (m, 1H), 5.08 (bs,    1H), 4.85 (bs, 1H), 2.82 (ddd, 1H, J=14.8, 9.5 and 6.3 Hz), 2.73 (d,    1H, J=12.6 Hz), 2.68-2.19 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.24    (m), 1.15 (m, 1H), 1.05 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz).    Measured mass [M+H]⁺437.3027. Calculated mass [M+H]⁺437.3050.-   c)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxodecyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel decanoate). ¹H-NMR (CDCl₃): δ 5.89 (bs, 1H), 5.08 (bs,    1H), 4.84 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz), 2.67-2.18    (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.21 (m), 1.15 (m, 1H), 1.06    (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Measured mass    [M+H]⁺479.3508. Calculated mass [M+H]⁺479.3519.-   d)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxoundecyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel undecanoate). ¹H-NMR (CDCl₃): δ 5.89 (m, 1H), 5.08    (bs, 1H), 4.85 (bs, 1H), 2.82 (ddd, 1H, J=14.8, 9.5 and 6.3 Hz),    2.73 (d, 1H, J=12.6 Hz), 2.68-2.18 (m), 2.63 (s, 1H), 2.11 (m, 1H),    1.90-1.21 (m), 1.06 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz).    Measured mass [M+H]⁺493.3664. Calculated mass [M+H]⁺493.3676.-   e)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxododecyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel dodecanoate). ¹H-NMR (CDCl₃): δ 5.89 (bs, 1H), 5.08    (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz),    2.65-2.18 (m), 2.64 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m,    1H), 1.06 (t, 3H, J=7.5 Hz), 0.88 (t, 3H, J=7.1 Hz). Measured mass    [M+H]⁺507.3829. Calculated mass [M+H]⁺507.3832.-   f)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxotridecyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel tridecanoate). ¹H-NMR (CDCl₃): δ 5.89 (bs, 1H), 5.08    (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz),    2.65-2.18 (m), 2.64 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m,    1H), 1.06 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz). Measured mass    [M+H]⁺521.4007. Calculated mass [M+H]⁺521.3989.-   g)    (17α)-13-Ethyl-11-methylene-17-[[(1-oxopentadecyl)oxy]-18,19-dinorpregn-4-en-20-yn-3-one    (etonogestrel pentadecanoate). ¹H-NMR (CDCl₃): δ 5.89 (bs, 1H), 5.08    (bs, 1H), 4.85 (bs, 1H), 2.82 (m, 1H), 2.73 (d, 1H, J=12.6 Hz),    2.65-2.19 (m), 2.63 (s, 1H), 2.11 (m, 1H), 1.90-1.20 (m), 1.15 (m,    1H), 1.06 (t, 3H, J=7.5 Hz), 0.89 (t, 3H, J=7.1 Hz). Measured mass    [M+H]⁺549.4278. Calculated mass [M+H]⁺549.4302.    Pharmacokinetics Studies in the Rabbit

For the determination of the pharmacokinetic profile of the differentetonogestrel-esters after parenteral application, i.m. application inthe castrated rabbit model was chosen instead of s.c. Briefly, rabbitswere injected once (day 1) with indicated etonogestrel-esters at 20mg/kg in arachis oil (with a concentration of 40 mg/ml). At day 1, 2, 3,4, 5, 6, 7, 8, 10, 12, 14, 21, 28, 35, 49, 63, 77, 92, 106, 120 and 133blood was collected from the ear arteria, in EDTA-containing tubes. EDTAplasma was prepared (1500 g, 15 min) and stored at −20° C. With LC-MSMS,the amount of parent compound (etonogestrel) was determined in thesesamples. The lower limit of this new assay is 0.5 nmol/l, from 0-250nmol/l a linear curve was obtained with a correlation coefficient of0.9998.

As shown in FIG. 2 a, etonogestrel itself resulted in very high peaklevels (200 nmol/l), which declined in 28 days to levels of etonogestrelbelow 1 nmol/l. Etonogestrel-heptanoate also gave rise to high initialpeak levels of etonogestrel (120 nmol/l). Etonogestrel-nonanoate gavelower peak levels and extended duration with serum levels ofetonogestrel above 1 nmol/l. As compared to the other two esters in FIG.2 a, etonogestrel undecanoate gave the most optimal balance betweeninitial peak levels (maximum of 13 nmol/l after eight days) and durationof action (more than 92 days above 1 nmol/l).

As shown in FIG. 2 b, etonogestrel decanoate gave an initial peak levelof 24 nmol/l after 5 days whereas etonogestrel dodecanoate gave aninitial peak level of 9 nmol/l after 8 days. With etonogestreltridecanoate, no initial levels of etonogestrel were observed.

From FIGS. 2 a and 2 b, it can be seen that preferred etonogestrelesters are etonogestrel decanoate, etonogestrel undecanoate, andetonogestrel dodecanoate.

Example 2 Kinetics of Two MENT Esters in Rabbits

The pharmacokinetic profile of MENT-undecanoate and MENT-buciclate wascompared to testosterone enanthate and testosterone undecanoate. FIG. 3shows the chemical structures of these androgen esters.

Ment-undecanoate was prepared essentially as described in WO 99/67271.MENT-buciclate was prepared as described in WO 99/67270. Testosteroneenanthate and undecanoate were commercially obtained from Diosynth, Oss,the Netherlands.

Pharmacokinetic Studies in the Rabbit

For the determination of the pharmacokinetic profile of the differentandrogen-esters after s.c. application, the castrated rabbit model wasselected as the model which is most similar to humans. Briefly, rabbitswere injected once (day 1) with indicated androgen-esters at 20 mg/kg inarachis oil (with a concentration of 100 mg/ml). At day 2, 3, 4, 5, 8,15, 22, 36, 44 and 58 blood was collected from the ear arteria, inEDTA-containing tubes. EDTA plasma was prepared (1500 g, 15 min) andstored at −20° C. With LC-MSMS, the amount of parent compound(testosterone or MENT) was determined in these samples. The lower limitof this new assay is 2 nmol/l, from 0-500 nmol/I a linear curve wasobtained with a correlation coefficient of 0.9998.

As shown in FIG. 4, both with MENT-undecanoate and MENT-buciclate apharmacokinetic profile of released MENT was found which is similar tothat of the reference compound testosterone undecanoate with respect toreleased testosterone. Testosterone enanthate resulted in a high peak oftestosterone 2 days after injection.

Thus, in the rabbit, with both MENT-esters no initial rise of MENT wasobserved on one hand and a prolonged release of MENT was observed on theother hand, suggestive for more optimal pharmacokinetic behaviour thanthe current standard testosterone enanthate. In humans, optimalpharmacokinetics were obtained with testosterone undecanoate: lowinitial release and steady-state levels of long duration (FIG. 5). Sincein rabbits the pharmacokinetic profile of the two MENT-esters was verysimilar to that of testosterone-undecanoate (FIG. 4), optimalpharmacokinetics with both MENT esters in humans is expected.

Example 3 Solubility and Viscosity of MENT-Undecanoate and EtonogestrelUndecanoate in Various Solvents

To determine the solubility and viscosity of MENT undecanoate andetonogestrel undecanoate, four different solvents were used:

-   -   ethyl undecanoate    -   ethyl undecanoate+50% benzyl benzoate    -   arachis oil    -   arachis oil+50% benzyl benzoate

Using these solvents, the following solutions were prepared:

-   -   100 mg/ml etonogestrel undecanoate in the different solvents    -   50 mg/ml etonogestrel undecanoate in the different solvents    -   200 mg/ml MENT undecanoate in the different solvents    -   100 mg/ml MENT undecanoate in the different solvents    -   50 mg/ml etonogestrel undecanoate+100 mg/ml MENT undecanoate in        the different solvents

The two combined solvents were prepared by addition of 50 gram of ethylundecanoate or arachis oil to 50 gram of benzyl benzoate. The ethylundecanoate+50% benzyl benzoate solution was filtered over a 0.22 μmDurapore filter to obtain a clear colourless solution. The arachisoil+50% benzyl benzoate solution was not filtered.

The solubility of the compounds in the solvents was determined visually.The viscosity was determined using a Brookfield model DV-III. Thedensity of the solutions was determined using a Mettler Toledo DA-100Mdensity meter. TABLE 1 Appearance, viscosity and density of the solventsSolvent Appearance Viscosity Density Ethyl undecanoate Clear colourlesssolution 2.6 0.861 Ethyl undecanoate + Clear colourless solution 3.90.975 50% benzyl benzoate Arachis oil Clear yellowish solution 64.10.913 Arachis oil + 50% Clear yellowish solution 22.9 1.007 benzylbenzoate Benzyl benzoate Clear yellowish solution 8.5 1.117

Ethyl undecanoate, ethyl undecanoate+50% benzyl benzoate and arachisoil+50% benzyl benzoate solutions did not need to be heated. To dissolve200 mg/ml MENT undecanoate in arachis oil, heating to approximately 50°C. was necessary.

The concentrations tested were 100 mg/ml etonogestrel undecanoate, 200mg/ml MENT undecanoate and 50 mg/ml etonogestrel undecanoate+100 mg/mlMENT undecanoate in the different solvents. The results are summarizedin table 2. TABLE 2 Appearance, viscosity and density of the finalsolutions Etonogestrel MENT undecanoate undecanoate Viscosity DensitySolvent (mg/ml) (mg/ml) Appearance (cps) (g/ml) Ethyl undecanoate 50 —Clear colourless solution 3.2 0.870 — 100 Clear colourless solution 4.00.879 50 100 Clear colourless solution 4.4 0.886 Ethyl undecanoate + 50— Clear colourless solution 4.7 0.978 50% benzyl benzoate — 100 Clearcolourless solution 6.1 0.979 50 100 Clear colourless solution 7.0 0.979Arachis oil 50 — Clear yellowish solution 76.6 0.919 — 100 Clearyellowish solution 97.2 0.924 50 100 Clear yellowish solution 99.7 0.935Arachis oil + 50% 50 — Clear yellowish solution 28.1 1.006 benzylbenzoate — 100 Clear yellowish solution 35.0 1.009 50 100 Clearyellowish solution 39.1 1.008

The combination of etonogestrel-undecanoate and MENT-undecanoate wasvisually dissolved at a desired concentration of 50 mg/mletonogestrel-undecanoate and 100 mg/ml MENT-undecanoate in all fourtested solvents. Both etonogestrel-undecanoate and MENT-undecanoatecould be dissolved at two times the desired concentration in all foursolvents tested. No precipitation occurred at room temperature when 50mg/ml etonogestrel-undecanoate and 100 mg/ml MENT-undecanoate weredissolved in all four solvents.

The viscosity of ethyl undecanoate and ethyl undecanoate+50% benzylbenzoate was significantly lower than the viscosity of arachis oil andarachis oil+50% benzyl benzoate. The viscosity of the desiredformulation 50 mg/ml etonogestrel undecanoate+100 mg/ml MENT undecanoatein the four different solvents was the lowest (4 cps) for the ethylundecanoate solution, followed by the ethyl undecanoate+50% benzylbenzoate (7 cps) and the arachis oil+50% benzyl benzoate solution (39cps). The viscosity of the arachis oil solution was significantly higherthat the viscosity of the other solutions (100 cps).

Example 4 Pharmacological Action of Etonogestrel Esters in the Male

The pharmacological action of etonogestrel esters in the male areevaluated for the suppressing activity of endogenous testosterone in therabbit as described in Wu, F. C., Balasubramanian, R., Mulders, T. M.and Coelingh-Bennink H. J., Oral progestogen combined with testosteroneas a potential male contraceptive: additive effects between desogestreland testosterone enanthate in suppression of spermatogenesis,pituitary-testicular axis, and lipid metabolism, J. Clin. Endocrinol.Metab 84 (1):112-122, 1999. Briefly, the effect of one sc/im injectionof the different etonogestrel esters on serum testosterone at day 7 ofmature male rabbits will be monitored.

Example 5 The Pharmacological Action of Etonogestrel Esters in theFemale

The pharmacological action of etonogestrel esters in the female aretested in the classical Clauberg test. Briefly, immature female rabbits,primed with oestradiol for 8 days, are treated once sc/im with thedifferent etonogestrel esters (day 8 afternoon). Autopsy is performed inthe afternoon of day 13 and the progestagenic activity is evaluated onsections of the uterine according to McPhail et al., The assay ofprogestin. J. of Physiology, 1934, 83:145-156.

Example 6 Needle-Less Administration of Arachis Oil in Human Volunteers

Arachis oil was administered by a needle-less device and by needle andsyringe to compare six parameters:

(1) completeness of injection; (2) injection pain; (3) injectionsensation; (4) local site reactions; (5) subject preference; and (6)systemic adverse effects.

Forty-eight (48) healthy men aged 18-70 were recruited for anopen-label, randomised, needle controlled trial. The men were dividedinto four groups:

Group 1: intramuscular injection with arachis oil and 10% benzyl alcoholwith a needle and a syringe IM (1.5 inch, 20 gauge needle)—hereinaftercalled device A

Group 2: subcutaneous injection with arachis oil and 10% benzyl alcoholwith a needle and a syringe S.C. (1.0 inch, 20 gauge needle)—hereinaftercalled device B

Group 3: intramuscular injection with arachis oil and 10% benzyl alcoholwith the needle-less device Medi-Jector Needle Free System (MJ7) IM (100lb. spring, 0.014 orifice (differential pressure)—hereinafter calleddevice C

Group 4: subcutaneous injection with arachis oil and 10% benzyl alcoholwith the needle-less device Medi-Jector Needle Free System (MJ7) S.C.(85 lb. spring, 0.011 orifice)—hereafter called device D

The men visited the clinic three times. During the first visit, the menwere trained how to self-inject in two injection sessions with twoinjections each separated by 2 hours. Each session was either with IM orS.C. needles or MediJector. The injections were randomised to right orleft and upper or lower thighs. The local site reaction (pain, itching,redness, swelling, bruising and sensation) was evaluated immediatelyafter each injection and for two hours thereafter and a patientpreference questionnaire was filled-out.

During the second visit, 24 hours later, the local site reaction and anyadverse experiences were evaluated. During the third visit, 5-7 dayslater, local site reactions and adverse experiences were againevaluated.

Completeness of Injection

To assess the completeness of injection, the following penetrationrating scale was used:

(1)—all of the oil penetrated the skin; (2S)—slight wetness on the skin;(2)—most of the oil penetrated the skin; (3)—about half the oilpenetrated the skin; (4)—very little of the oil penetrated the skin.

FIG. 6 shows the results. Most complete injection was achieved with theIM needle and thereafter with the IM MediJector (device A and Crespectively).

Injection Pain

To assess pain, a pain scale was used (FIG. 7). FIG. 8 clearly showsthat the least pain was experienced with the IM MediJector, and the mostpain with the IM Needle.

Injection Sensation

To assess injection sensation, a scale was used as presented in FIG. 9.FIG. 10 shows that both MediJector devices caused less injectionsensation.

Local Site Reactions

To assess the local site reactions, the following 4-point evaluationscale was used: 0—no reaction; 1—mild reaction; 2—moderate reaction;4—severe reaction

FIG. 11 shows the local site reactions after 2 hours, FIG. 12 after 24hours and FIG. 13 after 5-7 days.

Subject Preference

The patient preference questionnaire included the following questions:

Question 1—Overall I found the injections for device A,B,C,D

—very unpleasant; —somewhat unpleasant; —slightly unpleasant; —hardlyunpleasant; —not at all unpleasant.

Question 2—How willing would you be to have a doctor give you aninjection with device A,B,C,D

—very willing; —somewhat willing; —neutral; —somewhat unwilling; —veryunwilling.

Question 3—How willing would you be to give yourself an injection withdevice A,B,C,D

—very willing; —somewhat willing; —neutral; —somewhat unwilling; —veryunwilling.

Question 4-which device would you be most willing to use to giveyourself injections at home?

—IM Needle and Syringe (Device A); —S.C. Needle and Syringe (Device B);—IM-MediJector (Device C); S.C. MediJector (Device D).

FIG. 14 shows the results of the questionnaire.

Systemic Adverse Events

In total 7 adverse events were reported: 2 blisters and 5 crusts atinjection site. The events were all mild and involved all four devices.The events were probably related to the oil.

CONCLUSIONS

The above trial shows that S.C. administration of oil has somepercentage of wet injections.

IM and S.C. MediJectors were significantly less painful than needles.They were also considered more pleasant.

Even though MediJectors had a greater incidence of local site reactions(mild and clinically insignificant), subjects had a significantpreference for the needle-free MediJector.

In order to achieve a higher completeness of injection with IMMediJector, the spring force can be increased. Another possibility isthe use of a mini-needle device.

1-72. (canceled)
 73. An oily solution for injection to a subjectcomprising a 50-400 mg/ml of a long-acting progestogen and 25-200 mg/mlof a long-acting androgen dissolved in a pharmaceutically acceptableoily medium.
 74. A solution according to claim 1 wherein the long actingprogestogen is an ester with a fatty chain length of C7 to C15.
 75. Asolution according to claim 2 wherein the long acting progestogen is anester or a progestogen selected from the group consisting ofethisterone, norethisterone, dimethisterone, norethynodrel,norgestrienone, lynestrenol, ethynodiol, norgestrel, levo-norgestrel,desogestrel, gestodene, allylestrenol, etonogestrel and dienogest.
 76. Asolution according to claim 3 wherein the ester of progestogen isetonogestrel undecanoate.
 77. A solution according to claim 1 whereinthe long-acting androgen is an ester with a fatty chain length of C6 toC12.
 78. A solution according to claim 5 wherein the long-actingandrogen is an ester of testosterone or an ester of7-alpha-methyl-19-nortestosterone.
 79. A solution according to claim 6wherein the ester of the androgen is 7-alpha-methyl-19-nortestostetoneundecanoate.
 80. A solution according to claim 1 wherein the oily mediumis arachis oil or ethyl undecanoate.
 81. A needle-less device, amini-needle device or a pre-filled subcutaneous syringe, each forinjection administration by the subject himself, comprising less than 1millilitre of the solution according to claim 1.